Expression profiles and function of IL6 in polymorphonuclear myeloid-derived suppressor cells
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ORIGINAL ARTICLE
Expression profiles and function of IL6 in polymorphonuclear myeloid‑derived suppressor cells Mohammed L. Ibrahim1,2,3 · Chunwan Lu1,2,4 · John D. Klement1,2,4 · Priscilla S. Redd1,2,4 · Dafeng Yang1,2,4 · Alyssa D. Smith1,2,4 · Kebin Liu1,2,4 Received: 12 September 2019 / Accepted: 21 May 2020 © Springer-Verlag GmbH Germany, part of Springer Nature 2020
Abstract IL6 is an inflammatory cytokine with pleiotropic functions in both immune and nonimmune cells, and its expression level is inversely correlated with disease prognosis in patients with cancer. However, blocking IL6 alone has only yielded minimal efficacy in human cancer patients. We aimed at defining IL6 expression profiles under inflammatory conditions and cancer, and elucidating the mechanism underlying IL6 intrinsic signaling in colon carcinoma. We report here that colonic inflammation induces IL6 expression primarily in the CD11b+Ly6G+Ly6Clo polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC) in colon. Although both tumor cells, T cells and myeloid cells all express IL6, PMN-MDSCs are the primary cell type that express IL6 in colon carcinoma, suggesting that IL6 up-regulation is a response to inflammation in colon epithelium and tumor microenvironment. Furthermore, we determined that IL6 activates STAT3 to up-regulate DNMT1 and DNMT3b expression in colon tumor cells, thereby revealing an epigenetic mechanism that mediates the IL6-STAT3 signaling pathway in colon carcinoma. Surprisingly, knocking out IL6 in colon tumor cells did not significantly alter tumor growth in WT mice. Conversely, IL6-sufficient colon and pancreatic tumor grow at similar rate in WT and IL6-deficient mice. However, overexpression of IL6 in colon tumor cells significantly increases tumor growth in vivo. Our findings determine that a high tumor local IL6 threshold is essential for IL6 function in colon tumor promotion and targeting the IL6-expressing PMN-MDSCs is potentially an effective approach to suppress colon tumor growth in vivo. Keywords IL6 · DNMT · STAT3 · MDSCs · Colon tumor · Colonic inflammation
Introduction
Electronic supplementary material The online version of this article (https://doi.org/10.1007/s00262-020-02620-w) contains supplementary material, which is available to authorized users. * Kebin Liu [email protected] 1
Department of Biochemistry and Molecular Biology, Medical College of Georgia, 1410 Laney Walker Blvd, Augusta, GA 30912, USA
2
Georgia Cancer Center, Medical College of Georgia, Augusta, GA 30912, USA
3
Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Cairo University, Cairo, Egypt
4
Charlie Norwood VA Medical Center, Augusta, GA 30904, USA
Interleukin 6 (IL6) is a small glycoprotein that functions as a pleiotropic cytokine in both immune and nonimmune cells [1]. Unlike many other cytokines that have a restricted expression profile, IL6 is expressed in response to a broad variety of stimuli in a wide spectrum of cells [2–5]. At the cellular level, IL6 regulates the recruitment
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